Glioblastoma is the most common and aggressive primary brain tumor with median survival time of 14 months after diagnosis1. No effective treatment has been developed for glioblastoma patients yet. Recent studies have led to the hypothesis that glioblastomas are maintained by a small population of cancer stem cells that retain stem cell properties, are highly tumorigenic and resistant to radiotherapy and chemotherapy2-4. The cancer stem cell hypothesis proposes that a tumor comprises a cellular hierarchy, in which cancer stem cells reside at the top and have the ability to give rise to the heterogeneous populations of the tumor bulk5-7. The presence of these cancer stem cells together with the heterogeneity of the tumor mass renders glioblastoma treatment-resistant and recurring8. Therefore new therapies are needed to target these cancer stem cells4,9.
TLX (NR2E1) is a nuclear receptor expressed in vertebrate forebrains10 and essential for neural stem cell self-renewal,11,12. Recently, TLX has been shown to be expressed in human glioblastoma tissues and cell lines13,14, and play a role in glioblastoma development in mouse tumor models14. However, the function of TLX in human glioblastoma stem cells (GSCs)—initiated tumorigenesis and the effect of modulating TLX expression in human GSCs on the development of glioblastoma remain to be determined.
5-hydroxymethylcytosine (5hmC) is a form of DNA modification derived from hydroxylation of 5-methylcytosine (5mC). The level of 5hmC is considerably reduced in many types of human cancers15-17, including gliomas18-20. The level of 5hmC is tightly controlled by the TET family of dioxygenases, which catalyze the conversion of 5mC to 5hmC21,22. TET proteins have been shown to inhibit hematopoietic transformation23-25, breast and prostate cancer invasion and metastasis26. However the role of TET proteins, especially TET3, in glioblastoma tumorigenesis remains largely unknown.
Glioblastomas have been proposed to be maintained by highly tumorigenic GSCs that are resistant to current therapy. Therefore targeting GSCs is critical for developing effective therapies for glioblastoma. Novel insights described herein indicate the role of TET3 in TLX signalling. Compositions and methods of the present invention target the TLX-TET3 pathway to provide a novel therapy for brain cancers including glioblastoma.